Development of Thermo- and pH-Sensitive Liposomal Magnetic Carriers for New Potential Antitumor Thienopyridine Derivatives

Abstract

The development of stimuli-sensitive drug delivery systems is a very attractive area of current research in cancer therapy. The deep knowledge on the microenvironment of tumors has supported the progress of nanosystems’ ability for controlled and local fusion as well as drug release. Temperature and pH are two of the most promising triggers in the development of sensitive formulations to improve the efficacy of anticancer agents. Herein, magnetic liposomes with fusogenic sensitivity to pH and temperature were developed aiming at dual cancer therapy (by chemotherapy and magnetic hyperthermia). Magnetic nanoparticles of mixed calcium/manganese ferrite were synthesized by co-precipitation with citrate and by sol–gel method, and characterized by X-ray diffraction (XRD), scanning electron microscopy in transmission mode (STEM), and superconducting quantum interference device (SQUID). The citrate-stabilized nanoparticles showed a small-sized population (around 8 nm, determined by XRD) and suitable magnetic properties, with a low coercivity and high saturation magnetization (~54 emu/g). The nanoparticles were incorporated into liposomes of dipalmitoylphosphatidylcholine/cholesteryl hemisuccinate (DPPC:CHEMS) and of the same components with a PEGylated lipid (DPPC:CHEMS:DSPE-PEG), resulting in magnetoliposomes with sizes around 100 nm. Dynamic light scattering (DLS) and electrophoretic light scattering (ELS) measurements were performed to investigate the pH-sensitivity of the magnetoliposomes’ fusogenic ability. Two new antitumor thienopyridine derivatives were efficiently encapsulated in the magnetic liposomes and the drug delivery capability of the loaded nanosystems was evaluated, under different pH and temperature conditions.

Synthesis and Cytotoxicity Assessment of Citrate-Coated Calcium and Manganese Ferrite Nanoparticles for Magnetic Hyperthermia

“…The diffractograms were fitted to a cubic spinel phase (space group Fd3m, adapted from magnetite CIF 2300618), and using, as background, a set of 23 equally spaced points with adjustable intensities joined by linear regression lines. In general, the profiles displayed the well-defined peaks characteristic of a crystalline structure, and, as suggested by the good fitting from the Rietveld refinement, the Bragg's reflections characteristic of the Fd3m space group point out the presence of manganese/calcium ferrites with a cubic structure [12][13][14][15][16][17]. Notably, the presently employed method did not result in the formation of significant amounts of hematite as those reported in other sol-gel methods [14].…”

“…In general, the profiles displayed the well-defined peaks characteristic of a crystalline structure, and, as suggested by the good fitting from the Rietveld refinement, the Bragg's reflections characteristic of the Fd3m space group point out the presence of manganese/calcium ferrites with a cubic structure [12][13][14][15][16][17]. Notably, the presently employed method did not result in the formation of significant amounts of hematite as those reported in other sol-gel methods [14]. The average crystallite sizes were determined from the diffraction peak, with higher intensity corresponding to the reflection plane (3 1 1), using the Scherrer's equation [18]:…”

Development of pH-Sensitive Magnetoliposomes Containing Shape Anisotropic Nanoparticles for Potential Application in Combined Cancer Therapy

“…Furthermore, the lipid vesicles present a less negative zeta potential compared to solid magnetoliposomes, possibly due to the presence of MNPs near the bilayer surface, conferring an even more negative surface charge. In SMLs, the larger negative charge density on the surface (more negative zeta potential) may act to reduce the average diameter due to a decrease in aggregation [ 62 ]. Thus, the reductions in the hydrodynamic size, as well as in PDI and zeta potential, confirm the synthesis of solid magnetoliposomes and indicate suitable properties for biomedical applications, guaranteeing the enhanced permeability and retention (EPR) effect.…”

Perspective Chapter: Magnetoliposomes - A Recent Development as Recent Advances in the Field of Controlled Release Drug Delivery

“…The development of stimulus-sensitive DDS is a current area of cancer therapy research by Riberio et al, see [71]. The authors have developed magnetic liposomes adequate for temperature and pH-triggered anticancer drug release in the tumor environment in conjunction with magnetic hyperthermia.…”